After three years as a civil servant in the Senate office of the Interior, Wowereit stood for election as municipal councillor in the Tempelhof district. At the age of 30, he was, therefore, the youngest councilor in the city of Berlin. After eleven years as a District Councillor he stood for the Berlin House of Deputies (Abgeordnetenhaus von Berlin) which serves as the City's Landtag in 1995. In December 1999, he was elected chairman of the SPD parliamentary group in the Abgeordnetenhaus.

Since June 2001 he served as Governing Mayor (Regierender Bürgermeister) of Berlin. Previously, the SPD had left the grand coalition with the CDU and initiated new elections. After this election and following long-time negotiations, Wowereit finally started a coalition with the PDS.

In the elections held on 17 September 2006, Wowereit's SPD finished as the strongest party with a plurality of 30.8%. A coalition with Die Linke was continued. However the 16th Abgeordnetenhaus re-elected Wowereit as Governing Mayor on 23 November 2006, in the second ballot with only a 75:74 majority. CDU, Free Democrats and the Green Party voted against him. In the elections held on 18 September 2011 he and his party were again the strongest party.[2]

In 2011 he published Mut zur Integration – für ein neues Miteinander ("Courage for integration - for a new together"), a book written in response to the controversial book "Germany Abolishes Itself" written by former member of the Executive Board of the Deutsche Bundesbank - Thilo Sarrazin.[3]

On 26 August 2014 he announced that he would resign his position as of 11 December 2014.[4]

On 21 October 2003 Wowereit became one of four members representing the Land of Berlin in the supervisory board of the project to build the new Berlin Brandenburg Airport. In 2006, he was elected chairman of the board.[5] However, on 7 January 2013, Wowereit relinquished his chairmanship after the continuing delay of the airport's opening date.[6] The prime minister of the Land of Brandenburg, Matthias Platzeck was appointed as his successor.[7] Wowereit survived a vote of no confidence brought against him in the Berlin House of Representatives on 12 January. When Platzeck gave up his political offices for health reasons in July 2013, Wowereit was eventually appointed chairman again, despite much criticism.[8] Critics have accused Wowereit of being responsible for the various delays and cost overruns of the airport project. He has been accused of being blind to looming problems, and reacting angrily to unfavorable reports. Also, he is said to have filled the board with political friends rather than professionals.[9]

He announced his intention to resign at the end of 2014 due to the airport delays saying it was the "biggest failure" of his term in office, but that there were also other "several difficult times here."[10]

Wowereit is youngest to two brothers and two sisters and grew up without a father. One of his brothers supported his studies and later he took care of his brother, who was paralyzed after an accident, as well as his mother, who was suffering from cancer.

Wowereit is one of the most famous German politicians who is openly gay. In coming out, prior to the 2001 mayoral elections, he coined the now famous German phrase "Ich bin schwul, und das ist auch gut so." ("I'm gay, and that's that.") In his autobiography, Wowereit states that his decision to come out in public was made because after his nomination as candidate to become the Mayor of Berlin, he felt that the German tabloids were already "on the right track". With his coming out, Wowereit wanted to beat the tabloids to it and prevent them from writing wild, sensational and fabricated stories about his private life. Wowereit said those now famous words during a convention of the Berlin SPD. After the end of his speech, there was half a second of surprised silence, then spontaneous cheering and loud applause to support him.

In a 2010 interview with Time Magazine, he said that coming out may actually have strengthened his campaign.[11]

His election as mayor made Berlin one of three major European cities with an openly gay mayor, along with Paris, whose mayor was Bertrand Delanoë, and Hamburg, whose mayor was Ole von Beust at that time, who both also took office in 2001. However, von Beust resigned in 2010 and Delanoë left office in 2014, making Wowereit the only gay mayor of a major European and German city. Berlin being the largest and Hamburg being the second largest city in Germany, they are also German states in their own right, having made both Wowereit and von Beust also state premiers.

In September 2007, Wowereit published an autobiographical book titled "…und das ist auch gut so.", after his famous coming-out phrase (ISBN 3896673343).

Wowereit's civil partner, Jörn Kubicki, is a neurosurgeon. They have been in a relationship since 1993.